β-hairpin folding simulations in atomistic detail using an implicit solvent model 1 1Edited by F. Cohen

Žagrović, Bojan; Sorin, Eric J.; Pande, Vijay S.

doi:10.1006/jmbi.2001.5033

Cited by 264 publications

(307 citation statements)

References 43 publications

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“…Acidic and basic side chains were protonated by assuming neutral pH, and a chloride ion was added to account for charge neutrality (totaling 12,200 atoms in the system). Simulations were performed at constant temperature and pressure [298 K, 1 atm (1 atm ϭ 101.3 kPa)] with the GROMACS molecular dynamics suite (8) modified for the Folding@Home (7,14) infrastructure. The temperature and the pressure were controlled by coupling the system to an external heat bath with a relaxation time of 0.5 ps (15).…”

Section: Simulating Protein Folding On the Microsecond Time Scale In mentioning

confidence: 99%

“…In this work, both secondary and tertiary structure components were considered. Namely, we defined a conformation as fully folded when it had native-like secondary structure elements (a ␤-turn on residues 2-7 and an ␣-helix on residues [13][14][15][16][17][18][19][20] and an ␣-carbon root-mean-squared deviation (RMSD C␣ ) Ͻ3.1 Å from the NMR structure (9,10). This RMSD C␣ is one standard deviation above the average value of an ensemble of native conformations, which were generated from an independent set of simulations starting from the experimental native conformations (5,6).…”

Section: Simulating Protein Folding On the Microsecond Time Scale In mentioning

confidence: 99%

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Simulations of the role of water in the protein-folding mechanism

Rhee

Sorin

Jayachandran

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

195

229

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There are many unresolved questions regarding the role of water in protein folding. Does water merely induce hydrophobic forces, or does the discrete nature of water play a structural role in folding? Are the nonadditive aspects of water important in determining the folding mechanism? To help to address these questions, we have performed simulations of the folding of a model protein (BBA5) in explicit solvent. Starting 10,000 independent trajectories from a fully unfolded conformation, we have observed numerous folding events, making this work a comprehensive study of the kinetics of protein folding starting from the unfolded state and reaching the folded state and with an explicit solvation model and experimentally validated rates. Indeed, both the raw TIP3P folding rate (4.5 ؎ 2.5 s) and the diffusion-constant corrected rate (7.5 ؎ 4.2 s) are in strong agreement with the experimentally observed rate of 7.5 ؎ 3.5 s. To address the role of water in folding, the mechanism is compared with that predicted from implicit solvation simulations. An examination of solvent density near hydrophobic groups during folding suggests that in the case of BBA5, there are water-induced effects not captured by implicit solvation models, including signs of a ''concurrent mechanism'' of core collapse and desolvation.explicit solvation model ͉ distributed computing ͉ molecular dynamics W hen considering the nature of the protein folding mechanism, because of the dominance of the hydrophobic effect, one must consider the role of water. Water can be examined explicitly by studying discrete water molecules. However, it is common to consider the role of water implicitly in terms of its bulk dielectric property and interaction with hydrophobic groups of the protein. Implicit solvation methods have been widely adopted in the computational study of folding dynamics, where such dielectric and hydrophobic properties are accounted for with continuum models. In addition, it is interesting to consider that experiments assessing the folding mechanism (e.g., ⌽-value analysis) are typically interpreted in terms of an implicit role of water. For example, the stabilization or destabilization of protein-protein interactions is accounted for based on physical forces mediated by water, rather than an accounting of the role of specific, explicit water molecules.However, there are important properties of water which are not considered in typical implicit solvation models. In particular, the nonadditive nature of hydrophobicity leads to the so-called ''drying effect,'' in which a layer of vacuum surrounds hydrophobic surfaces and makes hydrophobic collapse cooperative (1). In addition, continuum models of water do not account for the discrete nature of water molecules, which may lead to differences in protein folding dynamics, such as a cooperative expulsion of water upon folding (2). It is also known that structured water plays a role in the folded state of many proteins (3). Accordingly, one can imagine that water may play a ''structural role'' in some o...

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Section: Simulating Protein Folding On the Microsecond Time Scale In mentioning

confidence: 99%

Section: Simulating Protein Folding On the Microsecond Time Scale In mentioning

confidence: 99%

Simulations of the role of water in the protein-folding mechanism

Rhee

Sorin

Jayachandran

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

195

229

View full text Add to dashboard Cite

show abstract

“…29 For example, even for a small 16-residue b-hairpin (GB1), there are debates over a hydrogen-bond zipping mechanism versus a hydrophobic core collapse mechanism. [30][31][32][33][34] In a separate example, even the use of high resolution experimental techniques such as coupling of H/D exchange with 2D NMR only allows detection of intermediate states with almost native-like five-strand b-sheet conformation during the earliest stage of Ubiquitin folding. 35,36 Computer simulations of protein models at different resolutions, from simple lattice models (and off-lattice) [37][38][39] to continuum solvent models 38,40,41 to all-atom explicit solvent models, 42,43 have been used to supplement existing experimental techniques in understanding aspects of protein folding.…”

Section: Introductionmentioning

confidence: 99%

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

2009

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Human age-onset cataracts are believed to be caused by the aggregation of partially unfolded or covalently damaged lens crystallin proteins; however, the exact molecular mechanism remains largely unknown. We have used microseconds of molecular dynamics simulations with explicit solvent to investigate the unfolding process of human lens cD-crystallin protein and its isolated domains. A partially unfolded folding intermediate of cD-crystallin is detected in simulations with its C-terminal domain (C-td) folded and N-terminal domain (N-td) unstructured, in excellent agreement with biochemical experiments. Our simulations strongly indicate that the stability and the folding mechanism of the N-td are regulated by the interdomain interactions, consistent with experimental observations. A hydrophobic folding core was identified within the C-td that is comprised of a and b strands from the Greek key motif 4, the one near the domain interface. Detailed analyses reveal a surprising non-native surface salt-bridge between Glu135 and Arg142 located at the end of the ab folded hairpin turn playing a critical role in stabilizing the folding core. On the other hand, an in silico single E135A substitution that disrupts this non-native Glu135-Arg142 salt-bridge causes significant destabilization to the folding core of the isolated C-td, which, in turn, induces unfolding of the N-td interface. These findings indicate that certain highly conserved charged residues, that is, Glu135 and Arg142, of cD-crystallin are crucial for stabilizing its hydrophobic domain interface in native conformation, and disruption of charges on the cD-crystallin surface might lead to unfolding and subsequent aggregation.

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“…Although REMD is a powerful method for exploring free energy landscapes, it does not provide direct information about kinetics. To study folding by using all-atom effective potentials, heterogeneous distributed computing (16,19) and transition path sampling (23, 24) techniques have been used. Although the former can enhance sampling by combining information from a large number of short MD trajectories ''steered'' by rare events, these techniques can introduce a bias toward fast events in the ensemble average of the reactive trajectories (25).…”

mentioning

confidence: 99%

Protein folding pathways from replica exchange simulations and a kinetic network model

Andrec

Felts

Gallicchio

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

140

167

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We present an approach to the study of protein folding that uses the combined power of replica exchange simulations and a network model for the kinetics. We carry out replica exchange simulations to generate a large (Ϸ10 6 ) set of states with an all-atom effective potential function and construct a kinetic model for folding, using an ansatz that allows kinetic transitions between states based on structural similarity. We use this network to perform random walks in the state space and examine the overall network structure. Results are presented for the C-terminal peptide from the B1 domain of protein G. The kinetics is two-state after small temperature perturbations. However, the coil-to-hairpin folding is dominated by pathways that visit metastable helical conformations. We propose possible mechanisms for the ␣-helix͞ ␤-hairpin interconversion.graph ͉ master equation ͉ protein G P rotein folding is a fundamental problem in modern structural biology, and recent advances in experimental techniques have helped to elucidate some of the thermodynamic and kinetic features that underlie different stages of the folding process (1-3). Computer simulations using reduced (4-11) and atomistic molecular models (12-21) have played a central role in the interpretation of experimental studies. Although reduced models have provided considerable insight into the overall mechanisms of protein folding, especially in helping to clarify the nature of folding funnels, intermediates, and kinetic bottlenecks, they are limited in their ability to explore the detailed molecular aspects of folding. However, because of the large number of degrees of freedom and the rarity of folding events even in small model systems, all-atom simulations require both considerable computational resources and ingenuity to obtain meaningful results; a variety of methods have been developed to increase simulation efficiency.A particularly powerful technique for the calculation of free energy surfaces and other thermodynamic properties of complex systems is replica exchange molecular dynamics (REMD) (22), in which a generalized ensemble of the system is simulated in parallel over a range of temperatures. Periodically, coordinates are exchanged by using a Metropolis criterion that ensures that at any given temperature a canonical distribution is realized and allows for more efficient barrier crossing than could be obtained with conventional simulation methods. Although REMD is a powerful method for exploring free energy landscapes, it does not provide direct information about kinetics. To study folding by using all-atom effective potentials, heterogeneous distributed computing (16,19) and transition path sampling (23, 24) techniques have been used. Although the former can enhance sampling by combining information from a large number of short MD trajectories ''steered'' by rare events, these techniques can introduce a bias toward fast events in the ensemble average of the reactive trajectories (25). Transition path sampling (23,24) can yield quantitative estimat...

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β-hairpin folding simulations in atomistic detail using an implicit solvent model 1 1Edited by F. Cohen

Cited by 264 publications

References 43 publications

Simulations of the role of water in the protein-folding mechanism

Simulations of the role of water in the protein-folding mechanism

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

Protein folding pathways from replica exchange simulations and a kinetic network model

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